To be effective, protein priming must induce the development of a distinct lineage of CD4⁺ T cells named T follicular helper (Tfh) cells, which regulate the differentiation of high‐affinity memory B cells and long‐lived plasma cells. In this context, we tested how adjuvantation with CpG, the Toll‐like receptor 9 agonist used in clinics, contributes to antigen‐specific T‐cell‐dependent B‐cell responses in vivo. We found that addition of CpG to other vaccine adjuvant increased the differentiation of antigen‐specific Tfh cells without changing the overall magnitude of the T‐cell response. This phenomenon correlated with an enhancement of the germinal centre reaction, antigen‐specific plasma cells and circulating antibodies. We comprehensively demonstrated that, in addition to the classical Tfh‐cell differentiation mediated by conventional DC, the promoting effect due to CpG was orchestrated in vivo by antigen presentation and IL‐6 secreted by monocyte‐derived dendritic cells (DC) as shown in their absence. Thus, while conventional DC initiate T‐cell responses, targeting monocyte‐derived DC specifically enhances the Tfh programme needed to regulate high‐affinity B‐cell protection in vivo.